Tumor Markers

Ferritin (FER) is a globulin composed of 24 light chains and heavy chains with a molecular weight of 450kDa. It is an important iron storage protein in eukaryotes, and its function is to maintain the soluble and non-toxic state of iron ions in the body. Ferritin is distributed throughout the body, especially in liver cells and reticuloendothelial cells, and exists in trace amounts in serum, which can reflect the iron ion content in the body. The determination of ferritin content is currently the most accurate way to detect iron deficiency. In fact, all patients with low serum iron and ferritin have iron deficiency. The serum ferritin content is an important indicator to distinguish iron-deficiency anemia (decreased serum ferritin) from chronic disease anemia (normal or elevated serum ferritin), and can also be used to distinguish microcytic anemia (low ferritin content) from mild thalassemia (normal or elevated ferritin content). Iron deficiency often occurs with a decrease in ferritin content during menstruation and childbearing age women and children. Patients with hemochromatosis, acute hepatitis, malignant tumors and chronic inflammatory diseases may also have an increase in serum ferritin content.

Human epididymis secretory protein E4 (HE4) belongs to the whey acidic 4-disulfide core (WFDC) protein family and has properties similar to pancreatic protease inhibitors. Under normal circumstances, HE4 is expressed at very low levels in the human body, but it is very high in the tissues and serum of ovarian cancer patients. It has high sensitivity for ovarian cancer detection, especially in the early asymptomatic stage. Human epididymal secretory protein 4 (HE4) is a new biomarker for ovarian cancer. It has important clinical significance for the early diagnosis, treatment monitoring and prognosis evaluation of ovarian cancer, and provides a more powerful basis for early diagnosis and treatment of ovarian cancer.

Alpha-fetoprotein (AFP) is a glycoprotein mainly synthesized in the fetal liver. At 13 weeks of gestation, AFP accounts for one-third of the total plasma protein, and reaches its peak at 30 weeks of gestation. It gradually decreases thereafter, and the concentration in plasma at birth is about 1% of the peak period, about 40 mg/L, which is close to the adult level at one year old (less than 30μg/L). AFP can enter the maternal blood circulation through part of the amniotic fluid. In maternal amniotic fluid or plasma, AFP can be used for prenatal monitoring of fetuses. For example, in cases of neural tube defects, spina bifida, anencephaly, etc., AFP can enter the amniotic fluid through open neural tubes and cause a significant increase in its content in the amniotic fluid. Fetal death in utero and teratoma can also cause an increase in AFP in amniotic fluid. In adults, AFP can be elevated in approximately 80% of patients with liver cancer serum. The positive rate of AFP in germ cell tumors is 50%. Different degrees of elevation may also occur in patients with pancreatic cancer or lung cancer and cirrhosis. When liver cells undergo malignant transformation, they recover their ability to produce this protein, and as the condition worsens, the content in serum will increase sharply. Alpha-fetoprotein has become a specific clinical indicator for the diagnosis of primary liver cancer.

Transferrin (TRF) is mainly synthesized by liver cells and is a single-chain glycoprotein with a molecular weight of about 79.6kD. TRF can reversibly bind multivalent cations such as iron, copper, zinc, and cobalt. The main physiological function of plasma TRF is to transport iron ions and belongs to negative acute phase reaction proteins. Transferrin can be used for differential diagnosis of anemia. In iron-deficiency (hypochromic) anemia, compensatory synthesis of TRF increases, but iron saturation is far lower than 30%. In aplastic anemia, TRF is normal or decreased, while iron saturation is increased; to determine nutritional status and liver function, it decreases in malnutrition and chronic liver disease. In nephrotic syndrome, TRF is lost in large amounts from urine and serum levels decrease.

Carbohydrate antigen 125 (CA125) is an important ovarian cancer-related antigen. It was discovered in 1981 by Bast et al. using ovarian cystadenocarcinoma cell lines to produce monoclonal antibody 0C125. CA125 is a large molecular weight polysaccharide protein with a molecular weight of> 200,000, which exists in epithelial ovarian cancer tissue and the serum of patients.

The chemical structure of carbohydrate antigen 50 (CA50) is CA19-9 without fucose. It is a type I lactose series tetrasaccharide sialylated, which generally does not exist in normal tissues. CA50 is a marker of pancreatic and colorectal cancer and is the most commonly used carbohydrate antigen tumor marker. Because it is widely present in the pancreas, gallbladder, liver, stomach, colon, bladder, and uterus, its tumor recognition spectrum is wider than that of CA19-9. Therefore, it is a common tumor marker-related antigen rather than a tumor marker specific to a certain organ. CA50 can be detected in different positive rates in various malignant tumors. The positive detection rate for pancreatic cancer and gallbladder cancer ranks first, accounting for 94.4%; others are liver cancer (88%), ovarian and uterine cancer (88%), and malignant pleural effusion (80%). It can be used for early diagnosis of tumors such as pancreatic cancer and gallbladder cancer, and has high value in the diagnosis of liver cancer, gastric cancer, colorectal cancer and ovarian tumors.

Carbohydrate antigen 19-9 (CA19-9), also known as gastrointestinal cancer-related antigen. In 1979, Koprowski used the single sialic acid ganglioside separated from the surface of human colon cancer cell line SW1116 as an antigen and made the corresponding monoclonal antibody 1116-NS-19-9. The tumor-related antigen recognized by this monoclonal antibody is called CA199, with a molecular weight of> 36,000. It also exists in normal secretions of humans such as saliva, semen, milk, and digestive juices.

Carbohydrate antigen 242 (CA242) levels are very low in normal people and benign tumor patients, but very high in patients with malignant tumors in multiple organs such as the digestive tract, especially in pancreatic cancer and colorectal tumors. It has high specificity and sensitivity for pancreatic and colorectal cancer and is the third-generation tumor marker for pancreatic and colorectal cancer. For the diagnosis of pancreatic cancer, CA242 is superior to CA19-9, with a sensitivity of 66%~100%, and the sensitivity of colorectal cancer is also 60%~72%. Combined with CEA and CA19-9 can improve the sensitivity of diagnosis of pancreatic cancer, colorectal cancer. CA242 is an auxiliary diagnostic marker for malignant tumors such as lung cancer and gastric cancer. CA242 can be used for early screening of tumors in normal populations.

carbohydrate antigen 72-4(CA72-4）is a tumor-associated glycoprotein (TAG-72) defined by two monoclonal antibodies (CC49 and B72.3). The first monoclonal antibody CC49 is an anti-high-purity TAG-72 antibody, and the second monoclonal antibody B72.3 is an antibody against the cell membrane of human metastatic breast cancer. CA72-4 is a marker for gastrointestinal tumors and ovarian cancer with a molecular weight of M400 000.

Squamous cell carcinoma antigen (SCC) is a glycoprotein with a molecular weight of 42,000. It is isolated from cervical squamous cell carcinoma tissue and belongs to the sub-segment of tumor-associated antigen TA-4. It exists in the cytoplasm of squamous cell carcinoma and is a better marker for squamous cell carcinoma tumors.

Neuron-specific enolase (NSE) is an isoenzyme of enolase. It is currently believed to be a tumor marker for small cell lung cancer (SCLC) and neuroblastoma. According to the different α, β, and γ subunits, the isoenzymes of enolase can be divided into five dimeric isoenzymes: αα, ββ, γγ, αβ, and αγ. The α subunit mainly exists in tissues such as liver and kidney; the β subunit mainly exists in skeletal muscle and myocardium; and the γ subunit mainly exists in nervous tissue. The isoenzyme composed of γγ subunits is unique to neurons and neuroendocrine cells, so it is named neuron-specific enolase. This enzyme has the highest content in normal human brain tissue and is also abnormally expressed in tumor tissues originating from neuroendocrine cells. Studies have found that SCLC is also a neuroendocrine tumor that can secrete NSE. NSE has a molecular weight of 87,000 and a pH of 4.7. It is an acidic protease that participates in glycolysis. Its main function is to catalyze phosphoglycerate into enolpyruvate phosphate. The glycolysis of cancerous tissues is enhanced, the cell proliferation cycle is accelerated, and the release of NSE into the blood increases, leading to an increase in the content of this enzyme in serum. NSE also exists in normal red blood cells and platelets. Hemolysis of specimens will affect the measurement results, so special attention should be paid to avoid hemolysis when collecting blood.

PSA has strong organ specificity. Although it can increase in benign prostate diseases such as prostate cancer hypertrophy and prostatitis, it still plays an important role in screening, auxiliary diagnosis, therapeutic effect monitoring, and recurrence prediction of prostate cancer. It can be used as an auxiliary diagnostic tool for the differential diagnosis of benign and malignant prostate diseases. Elevated PSA levels can be seen in diseases such as prostate cancer, prostate hypertrophy, and prostatitis. After prostate cancer surgery, t-PSA levels can return to normal. If the t-PSA concentration does not decrease after surgery or decreases and then increases again, it indicates tumor metastasis or recurrence. The f-PSA level in prostate cancer patients is lower than that in normal and benign diseases. Therefore, the f-PSA/t-PSA ratio can be used as a diagnostic indicator for prostate cancer. When f-PSA/t-PSA <15%, it highly suggests that there is a change to prostate cancer and is the distinguishing point between benign and malignant prostate diseases.

Prostate-specific antigen (PSA) was first reported by Wang in 1979. It is a protease secreted by prostate epithelial cells and is a single-chain glycoprotein with a molecular weight of 34,000. The content of PSA in normal human serum is extremely low. The normal glandular structure of prostate cancer patients is destroyed, and the PSA content in serum can increase. Currently, it has been widely used for the auxiliary diagnosis of prostate cancer in clinical practice, but PSA can also increase slightly in benign prostate diseases. In total PSA (t-PSA) in serum, 80% of PSA exists in various forms of combination, called complex PSA (c-PSA); 20% of PSA exists in an unbound form, called free PSA (f-PSA).

Pepsinogen (PG) is synthesized by the main cells of the acid-secreting gland and is converted into pepsin in the stomach cavity by hydrochloric acid (HCL) or active pepsin. Pepsin breaks down proteins into fat, amino acids, and small amounts of polypeptides. PG is a protein polypeptide chain composed of 375 amino acids, with an average relative molecular weight of 42kDa. There are seven groups of gastric protein isoenzymes in human gastric mucosa. According to their biochemical properties and immunogenicity, they are divided into two subgroups. Immunogenicity of groups 1-5 is the same and is called pepsinogen I (PGI, PGA), which is mainly secreted by the main cells and mucous neck cells of the gastric fundus gland; components 6 and 7 are called pepsinogen II (PGII, PGB), which are secreted by the main cells and mucous neck cells of the gastric fundus gland as well as the mucous neck cells of the cardia gland and pyloric gland in the stomach and the upper part of the duodenum. Serum PG I and PG II reflect the number of gastric mucosal glands and cells and indirectly reflect the secretion function of different parts of the gastric mucosa. When pathological changes occur in the gastric mucosa, serum PG content also changes accordingly. Therefore, monitoring the concentration of PG in serum can be used as a means to monitor the status of gastric mucosa. In 2017, “Chinese Consensus on Chronic Gastritis” highly affirmed the value of PG. The guidelines gave the following recommendations: detection of serum pepsinogen (PG) I, II, and gastrin 17 can help determine whether there is atrophy of gastric mucosa and its degree. At the same time, “Chinese Expert Consensus on Early Gastric Cancer Screening Process” further proposed a new gastric cancer screening scoring system. Among them, advanced age, male gender, HP antibody positive, low pepsinogen ratio (PGR), high serum G17 level are high-risk factors for gastric cancer.

Gastrin is a gastrointestinal hormone mainly secreted by the G cells of the gastric antrum and duodenum. It plays an important role in regulating gastrointestinal function and maintaining its structural integrity. More than 95% of biologically active gastrin in the human body is α-amidated gastrin, which mainly contains two isomers G17 and G34. Among them, 80%~90% is G17 composed of 17 amino acid residues. G17 is only secreted by the G cells of the gastric antrum, so it is an important indicator reflecting the damage of gastric mucosa. Human serum gastric function detection based on G17 as the core indicator is a non-invasive, painless, safe, economical human gastric disease detection method. This detection project can effectively reduce the risk of gastric cancer and greatly improve the early diagnosis and treatment probability of gastric cancer. It has important positive significance for the prevention and treatment of various gastric diseases. “Chinese Consensus on Chronic Gastritis 2017” clearly states that detection of serum pepsinogen (PG) I, PG II and G17 can help determine whether there is atrophy of gastric mucosa and its degree. “Chronic Gastritis Primary Diagnosis and Treatment Guidelines (Practice Edition 2019)” further clarifies that detection of serum pepsinogen (PG) I, PG II and G17 can help diagnose chronic atrophic gastritis. If PG I, PG I/PG II ratio decreases and serum G17 level increases, it indicates that gastric body atrophy is dominant; if PG I and PG I/PG II ratio are normal and serum G17 level decreases, it indicates that gastric antrum atrophy is dominant; if the whole stomach atrophies, both PG and G17 decrease.

Helicobacter pylori (Hp) is a bacterium parasitic in the stomach, adhering to the gastric mucosa and intercellular space. At present, the infection rate of Hp in China is about 50%. Hp infection is currently the most clear risk factor for gastric cancer. Humans are the only source of Helicobacter pylori infection, mainly hidden in saliva, dental plaque, stomach and feces. Helicobacter pylori (Hp) can secrete toxins to damage human cells, causing inflammation, ulcers and tumors. Helicobacter pylori has multiple virulence factors, including flagellin subunit A and B, vacuolating cytotoxin (VacA), cytotoxin-associated gene A and CagA, urease subunit A and B. Helicobacter pylori is the only bacterium in human stomach that can produce a large amount of urease. Therefore, it can diagnose Helicobacter pylori infection by detecting urease.

MMP-3 is a member of the matrix metalloproteinase superfamily, which is a type of protease that can degrade extracellular matrix. It exists in normal human body and participates in the degradation of cartilage matrix and bone absorption in extracellular matrix. MMP-3 can act on PG, LN, FN, type III and IV collagen and gelatin. Its activity is regulated at three levels: gene transcription level, inactive enzyme precursor activation by protein hydrolysis and specific inhibition factor (TIMP). MMP3 is a reliable biomarker for disease activity, imaging monitoring, disease outcome prediction and treatment response in rheumatoid arthritis, as well as a new predictor of coronary heart disease. It can also be used as a prognostic monitoring index and for monitoring drug treatment effects. MMP-3 is closely related to the occurrence and development of breast cancer and plays an important role in the infiltration and metastasis of breast cancer. The serum MMP-3 level of patients with ankylosing spondylitis is significantly higher than that of normal people, which can effectively reflect the disease activity and bone joint destruction degree of patients and provide scientific basis for clinical judgment, disease progression and treatment efficacy.

S100β is a central nervous system-specific protein that was first discovered in bovine brain tissue by Moore et al. in 1965. It is mainly produced by astrocytes and exists in the central nervous system in the form of dimeric activity through cysteine residues forming disulfide bonds. About 96% of it exists in the brain. When the brain is damaged or the blood-brain barrier is damaged, the cerebrospinal fluid content rapidly increases and enters the peripheral blood through the blood-brain barrier. Therefore, serum S100β protein can be used as an early marker of central nervous system damage, also known as the “C-reactive protein” of brain damage. The “2016 Chinese Expert Consensus on Cardiopulmonary Resuscitation” recommends the use of S100β to detect and protect nerve function. S100β protein also appears to be partially elevated in some malignant tumors, such as malignant melanoma, breast cancer, renal cancer, gastric cancer and ovarian cancer. Combined with other indicators, it can screen out high-risk groups of malignant tumor patients. The “Diagnosis and Treatment Specification for Melanoma” (2018 edition) recommends that S100β protein be used as a screening indicator for melanoma.

CYFRA21-1 is widely distributed on the surface of normal tissues and single layer epithelial cells. CYFRA21-1 is mainly used for the detection of non-small cell lung cancer, and has a certain positive rate for other invasive bladder cancer,such as ,nasopharyngeal cancer, breast cancer, liver cancer, cervical cancer and digestive tract tumors. It also has a certain degree of elevation in hepatitis, pancreatitis, pneumonia, but usually not more than 10ng/ml.

Human pro-gastrin-releasing peptide（ProGRP） is a lung cancer tumor marker that is commonly used for the early diagnosis of lung cancer as well as to determine whether lung cancer has recurred.

GPC3 is overexpressed in some types of tumors, especially hepatocellular carcinoma (HCC).It has been established in patients with HCC that the prognostic significance of serum GPC3 levels and GPC3 immunoreactivity in tumor cells . In addition to its usefulness as a biomarker, GPC3 is also attracting attention as a novel therapeutic target molecule, and clinical trials targeting GPC3 ongoing.

CEA was originally found in colon cancer and fetal intestinal tissue, hence the name carcinoembryonic antigen. Elevated CEA was commonly seen in colorectal cancer, pancreatic cancer, gastric cancer, small cell lung cancer, breast cancer, and medullary thyroid cancer. However,it will also be elevated serum CEA that the 15% to 53% patients ,which is smoking, pregnancy and cardiovascular disease, diabetes, non-specific colitis and other diseases. So CEA is not a specific marker of malignant tumors and only auxiliary value in diagnosis. In addition, there was a clear relationship between the serum CEA level and the stage of colorectal cancer, the more advanced the lesion, the higher the CEA concentration.

A large number of studies have shown that Golgi protein 73 appears earlier than alpha-fetoprotein, and the sensitivity is significantly higher than the latter in early diagnosis of HCC. Therefore, the National Ministry of Health has included the determination of Golgi protein 73 in the diagnosis and treatment of primary liver cancer in 2011. Golgi 73 is a transmembrane protein present in the Golgi apparatus, and has gradually become a serum marker for the diagnosis of liver cancer, especially early liver cancer.